Many polymeric materials have been used as components of devices for diagnosis or therapy, where they have had a significant impact on the clinical success of implant technology. These materials have been used, for example, as orthopedic devices, ventricular shunts, drug-carriers, contact lens', heart valves, sutures, and burn dressings. These polymers can be non-biodegradable or biodegradable.
In traditional drug delivery, it has long been recognized that tablets, capsules, and injections may not be the best mode of administration. These conventional routes often involve frequent and repeated doses, resulting in a "peak and valley" pattern of therapeutic agent concentration. Since each therapeutic agent has a therapeutic range above which it is toxic and below which it is ineffective, a fluctuating therapeutic agent concentration may cause alternating periods of ineffectiveness and toxicity. For this reason, controlled release provides a way of maintaining the therapeutic agent level within the desired therapeutic range for the duration of treatment. Using a polymeric carrier is one effective means to deliver the therapeutic agent locally and in a controlled fashion (Langer, et al., Rev. Macro. Chem. Phys., C23(1), 61, 1983). Such systems require less total drug and, as a result, systemic side effects can be minimized.
Polymers have been used as carriers of therapeutic agents to effect a localized and sustained release (Controlled Drug Delivery, Vol. I and II, Bruck, S.D., (ed.), CRC Press, Boca Raton, Fla., 1983; Leong, et al., Adv. Drug Delivery Review, 1:199, 1987). These therapeutic agent delivery systems simulate infusion and offer the potential of enhanced therapeutic efficacy and reduced systemic toxicity.
For a non-biodegradable matrix, the steps leading to release of the therapeutic agent are water diffusion into the matrix, dissolution of the therapeutic agent, and out-diffusion of the therapeutic agent through the channels of the matrix. As a consequence, the mean residence time of the therapeutic agent existing in the soluble state is longer for a non-biodegradable matrix than for a biodegradable matrix where a long passage through the channels is no longer required. Since many pharmaceuticals have short half-lives it is likely that the therapeutic agent is decomposed or inactivated inside the non-biodegradable matrix before it can be released. This issue is particularly significant for many bio-macromolecules and smaller polypeptides, since these molecules are generally unstable in buffer and have low permeability through polymers. In fact, in a non-biodegradable matrix, many bio-macromolecules will aggregate and precipitate, clogging the channels necessary for diffusion out of the carrier matrix. This problem is largely alleviated by using a biodegradable matrix which allows controlled release of the therapeutic agent. Biodegradable polymers differ from non-biodegradable polymers in that they are consumed or biodegraded during therapy. This usually involves breakdown of the polymer to its monomeric subunits, which should be biocompatible with the surrounding tissue. The life of a biodegradable polymer in vivo depends on its molecular weight and degree of cross-linking; the greater the molecular weight and degree of crosslinking, the longer the life. The most highly investigated biodegradable polymers are polylactic acid (PLA), polyglycolic acid (PGA), polyglycolic acid (PGA), copolymers of PLA and PGA, polyamides, and copolymers of polyamides and polyesters. PLA, sometimes referred to as polylactide, undergoes hydrolytic de-esterification to lactic acid, a normal product of muscle metabolism. PGA is chemically related to PLA and is commonly used for absorbable surgical sutures, as is the PLA/PGA copolymer. However, the use of PGA in controlled-release implants has been limited due to its low solubility in common solvents and subsequent difficulty in fabrication of devices.
An advantage of a biodegradable material is the elimination of the need for surgical removal after it has fulfilled its mission. The appeal of such a material is more than simply for convenience. From a technical standpoint, a material which biodegrades gradually and is excreted over time can offer many unique advantages.
A biodegradable therapeutic agent delivery system has several additional advantages: 1) the therapeutic agent release rate is amenable to control through variation of the matrix composition; 2) implantation can be done at sites difficult or impossible for retrieval; 3) delivery of unstable therapeutic agents is more practical. This last point is of particular importance in light of the advances in molecular biology and genetic engineering which have lead to the commercial availability of many potent bio-macromolecules. The short in vivo half-lives and low GI tract absorption of these polypeptides render them totally unsuitable for conventional oral or intravenous administration. Also, because these substances are often unstable in buffer, such polypeptides cannot be effectively delivered by pumping devices.
In its simplest form, a biodegradable therapeutic agent delivery system consist of a dispersion of the drug solutes in a polymer matrix. The therapeutic agent is released as the polymeric matrix decomposes, or biodegrades into soluble products which are excreted from the body. Several classes of synthetic polymers, including polyesters (Pitt, et al., in Controlled Release of Bioactive Materials, R. Baker, Ed., Academic Press, New York, 1980); polyamides (Sidman, et al., Journal of Membrane Science, 7:227, 1979); polyurethanes (Maser, et al., Journal of Polymer Science, Polymer Symposium, 66:259, 1979); polyorthoesters (Heller, et al., Polymer Engineering Science, 21:727, 1981); and polyanhydrides (Leong, et al., Biomaterials, 7:364, 1986) have been studied for this purpose.
All prior art biodegradable polymers possess some degree of imperfection such as weak mechanical strength, unfavorable degradation characteristics, toxicity, inflexibility, or fabrication difficulty. Although these biodegradable polymers have a broad range of potential utility, there is no one single material available that could satisfy all requirements imposed by different applications. Accordingly, there is a definite need to develop new biodegradable polymers.
The biodegradable matrix of the invention finds broad utility as a transient prosthetic support in orthopedic applications. For centuries, physicians have attempted to repair and replace various components of the skeletal system. These attempts have utilized various kinds of materials including bone, ivory, collagen, wood, metals, alloys, ceramics, glasses, corals, carbons, polymers, and composites of materials as bone prostheses.
Ideally, the bone prosthesis should be a material that is biologically inert, readily available, easily adaptable to the site in terms of shape and size, and replaceable by the host bone. Replacement of the prothesis by the host bone necessitates that the substitute be biodegradable.
The different elastic moduli of the prior art prosthetic implants versus that of bone often causes cortical bone to atrophy. The theoretical advantage of gradual load transfer from the bone plate to the bone and the elimination of the need for surgical removal after the healing of a fracture would make an absorbable osteosynthetic material extremely useful. As a temporary support in a load-bearing area of an articular joint, a resorbable porous material also has the advantage of preventing further destruction of cartilage defects and promoting bone and cartilage-forming cells. Hence, a need exists for a biodegradable prosthesis of sufficient post-implantation strength and rigidity to provide structural support.
European Patent Application 0386,757 (published Dec. 9, 1990), which is hereby incorporated by reference, discloses a new class of poly(phosphate esters). These polymers are biocompatible and biodegradable, and find application as prostheses, drug delivery devices, and other biomedical materials.
Polyurethanes, because of their excellent mechanical strength and good blood and tissue compatibility, have been used in a number of prosthetic devices. Biodegradable polyurethanes have also attracted considerable interest, as described in Bruin P., et al., Biomaterials, 11:291, 1990. While such biodegradable polymers have promise for use in a controlled drug delivery device, these prior art polymers have been of limited usefulness because of their slow degradation rate. Consequently, the need for new polyurethane materials which can be used to fabricate prostheses or drug delivery devices continues to exist.